Keratinocyte integrin 3131 induces expression of the macrophage stimulating factor, CSF-1, through a YAP/TEAD-dependent mechanism

The development of wound therapy targeting integrins is hampered by inadequate understanding of integrin function in cutaneous wound healing and the wound microenvironment. Following cutaneous injury, keratinocytes migrate to restore the skin barrier, and macrophages aid in debris clearance. Thus, both keratinocytes and macrophages are critical to the coordination of tissue repair. Keratinocyte integrins have been shown to participate in this coordinated effort by regulating secreted factors, some of which crosstalk to distinct cells in the wound microenvironment. Epidermal integrin alpha 3131 is a receptor for laminin-332 in the cutaneous basement membrane. Here we show that wounds deficient in epidermal alpha 3131 express less epidermal-derived macrophage colony-stimulating factor 1 (CSF-1), the primary macrophage-stimulating growth factor. alpha 3131-deficient wounds also have fewer wound-proximal macrophages, suggesting that keratinocyte alpha 3131 may stimulate wound macrophages through the regulation of CSF-1. Indeed, using a set of immortalized keratinocytes, we demonstrate that keratinocyte-derived CSF-1 supports macrophage growth, and that alpha 3131 regulates Csf1 expression through Srcdependent stimulation of Yes-associated protein (YAP)-Transcriptional enhanced associate domain (TEAD)mediated transcription. Consistently, alpha 3131-deficient wounds in vivo display a substantially reduced number of keratinocytes with YAP-positive nuclei. Overall, our current findings identify a novel role for epidermal integrin alpha 3131 in regulating the cutaneous wound microenvironment by mediating paracrine crosstalk from keratinocytes to wound macrophages, implicating alpha 3131 as a potential target of wound therapy.